Recently, there has been a revolution in biotechnology that is producing an abundance of potent new protein, peptide, and DNA-based drugs. Efficient, convenient, and effective means of delivering such therapeutics, however, are still needed.
Man has inhaled drugs for medicinal, recreational, and other purposes for centuries. Today's smokers, drug abusers, and asthmatics know that inhaled drugs act quickly, minimize the dose required, and are non-invasive. In fact, inhalation of aerosolized drugs has become a well-established means of treating localized disease states within the lung, including the millions of people in the U.S. that use fast-acting inhaled β2-agonists as treatment for unexpected asthma attacks. It has recently been demonstrated that the lung may be an ideal site for the non-invasive delivery of therapeutic molecules, including peptides and proteins, to the systemic circulation as well. Insulin, calcitonin, interferons, parathyroid hormone, and leuprolide are examples of proteins in clinical studies for systemic action following inhalation. The lung is an attractive route for drug delivery owing to its enormous surface area for absorption (˜100–140 m2), highly permeable epithelium compared with the gastrointestinal tract, and favorable environment for protein drugs compared to the low pH and high protease levels associated with oral delivery. In addition, pulmonary drug delivery avoids first pass hepatic metabolism and is generally more acceptable to patients than an injection.
Although promising, delivery of therapeutics to the lungs faces several anatomical and physiological challenges. To deposit in the lungs, drugs must traverse a complex lung structure that is heterogeneous in geometry and environment from patient to patient. Once deposited, natural clearance methods, including the “mucociliary escalator”, work to expel particles from the upper airways, while alveolar macrophages rapidly (often within minutes) engulf particles between 1 and 5 μm that reach the deep lungs. Additional drug loss can occur in the inhaler device due to inefficient aerosolization, or in the mouth, throat, and upper airways due to suboptimal aerosol characteristics or improper coordination of aerosol activation and breathing. Consequently, aerosol design is vital to maximize delivery efficiency and eliminate irreproducibility that can limit the practicality of new pulmonary therapies.
Pulmonary drug delivery methods have traditionally focused on one of two strategies: (i) drug suspension/dissolution in liquid aerosol drops and (ii) mixtures of dry drug particulates with dry carrier particles typically composed of sugars. These methods, capable of delivering medicine quickly to the bloodstream or local tissue, have been studied for treatments ranging from asthma and pain relief to influenza. Although effective as immediate relief therapies, an inability to achieve sustained drug delivery with traditional methods has limited the scope of inhaled medicines.
The use of controlled release polymeric systems is an approach that holds promise for improving the duration and effectiveness of inhaled drugs, for both local and systemic action. Micrometer- and nanometer-sized polymeric systems have been used to deliver precise amounts of drugs, including proteins and genes, over prolonged times to local tissues or the systemic circulation following injection. Biodegradable microparticles have been shown to be a suitable delivery vehicle.
However, a number of problems must be addressed to formulate successful microparticles aerosol delivery systems. These problems include the high loss of inhaled aerosol in non-absorptive areas of the lung and removal of microparticles due to phagocytosis by lung macrophages. Mechanisms of reducing phagocytosis of microparticles administered intravenously have been actively investigated. One successful strategy has been coating the surfaces of microparticles with poly(ethylene glycol) (PEG). Also, it has recently been shown that large (5–20 μm), low density (<0.1 g/cc) dry powder aerosols can be efficiently aerosolized into the deep lungs. Large particle size dramatically reduces particle clearance rates by phagocytic cells, allowing them to remain in the deep lungs and deliver drugs for extended periods of time.
Although promising, inhalation drug therapy is limited by low particle-delivery efficiencies to the absorptive portion of the lungs (deep lungs or alveolar region) and by the short duration of action of medications in aerosol form. As a result, most current medical aerosols require inhalation 3–4 times a day to provide desired clinical effects.
Initial studies with polymeric aerosol systems showed that properly engineered, large porous particles (LPP) were also capable of delivering bioactive insulin to the blood of rats and control glucose levels for 96 hours. The previous longest sustained delivery of insulin to the blood via the lungs was only 6 hours, using liposomes that were intratracheally instilled into rat lungs. Since then, only limited examples of polymeric aerosol systems have been reported. For example, respirable poly(lactic-co-glycolic) acid (PLGA) microspheres containing rifampicin for the treatment of tuberculosis have been studied in a guinea pig model. Cationic polymers, such as polyethyleneimine (PEI) and poly-L-lysine (PLL), complexed with DNA have also been tested in the airways as a method to achieve transient gene expression. Although promising, transient gene expression would also require frequent administration to maintain a therapeutic effect. Properly designed new polymeric aerosols, with the ability to target various regions of the lung, should prove beneficial for prolonged non-invasive treatment of both lung disorders, such as asthma or cystic fibrosis, and diseases requiring drug delivery to the systemic circulation.
Most previous studies of polymeric pulmonary drug delivery have utilized PLGA since it is readily available and has a long history of safety in humans. However, PLGA has many limitations as a carrier for drugs in the lungs. First, small PLGA microspheres degrade over the period of weeks to months, but typically deliver drugs for a shorter period of time. Such a pattern can lead to an unwanted build up of polymer in the lungs upon repeat administration. Second, bulk degradation of PLGA microspheres creates an acidic core, which can damage pH sensitive drugs such as peptides and proteins. Surface eroding polymers, such as polyanhydrides, lessen the effect of acidic build-up by increased diffusion rates of soluble fragments away from the particle. Third, PLGA microspheres have hydrophobic surfaces, which result in sub-optimal particle flight into the deep lung (due to particle agglomeration by van der Waals forces). Additionally, hydrophobic surfaces lead to rapid opsonization (protein adsorption), resulting in a rapid clearance by alveolar phagocytic cells. As a result, alternative polymer matrices would be useful for pulmonary administration of pharmaceuticals, as well as for sustained release delivery by other routes.